Calcium overload-induced apoptosis in cancer cells: ER-mitochondria crosstalk and therapeutic implications

Calcium overload exhibits significant anti-tumor potential by inducing abnormal intracellular Ca²⁺ accumulation, which disrupts mitochondrial and endoplasmic reticulum (ER) functions, thereby triggering apoptosis. However, its clinical application is currently hindered by challenges such as poor tumor-targeting capabilities, insufficient tumor accumulation, and incomplete mechanistic understanding. This review systematically analyzes the structural and functional coupling between the ER and mitochondria to elucidate the mechanisms of calcium overload-mediated cell death. We highlight how Ca²⁺ acts as a critical trigger to amplify mitochondria-associated ER stress, fostering a self-amplifying loop of crosstalk that initiates tumor cell death pathways. Furthermore, we summarize recent advances in targeted Ca²⁺ delivery using calcium-based nanocarriers combined with emerging modalities like sonodynamic therapy (SDT) and photothermal therapy (PTT), highlighting their synergistic antitumor potential. Compared with previous reviews, this work focuses on recent calcium-based nanosystems, sequential ER-mitochondria damage during Ca²⁺ overload, the MAM-associated IP3R-GRP75-VDAC1-MCU axis, and future strategies for tumor-targeted, TME-responsive, and multimodal synergistic therapy. By summarizing current research, this review aims to provide a prospective outlook for the novel anti-cancer therapies that target the disruption of intracellular Ca²⁺ homeostasis.